Pitavastatin Monograph

Pitavastatin (Livalo®)
National Drug Monograph
January 2012
VA Pharmacy Benefits Management Services,
Medical Advisory Panel, and VISN Pharmacist Executives

The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary
decisions. These documents will be updated when new clinical data warrant additional formulary discussion.
Documents will be placed in the Archive section when the information is deemed to be no longer current.

Executive Summary1-34
Description
Pitavastatin (Livalo®) was approved by the FDA in August 2009 for use in patients with primary
hyperlipidemia and mixed dyslipidemia as an adjunct to diet for reducing total cholesterol, low-density
lipoprotein, apolipoprotein B and triglycerides and to increase high-density lipoprotein.

Efficacy (LDL lowering)


In premarketing studies, pitavastatin was shown to reduce low-density lipoprotein cholesterol
(LDL) anywhere from 31-45% (pitavastatin 1-4 mg), with pitavastatin 2 mg being non-
inferior to atorvastatin 10 mg and simvastatin 20 mg. This resulted in a similar proportion of
patients achieving their LDL targets with pitavastatin 2 mg as compared to atorvastatin 10 mg
(92.7% vs. 92%; p = NS) and simvastatin 20 mg (93.9% vs. 91.3%; p = 0.709, respectively). 3
In terms of other lipid parameters, pitavastatin decreased total cholesterol (TC) by 22-32%,
triglycerides (TG) by 13-22% and increased high-density lipoprotein (HDL) cholesterol by 1-
8%.

In post-marketing clinical studies, pitavastatin reduced LDL, Total Cholesterol (TC), non-
HDL cholesterol and Apolipoprotein B (ApoB) by 26.2-48%, 16.6-37%, 22.5-45%, and 17.4-
41%, respectively. Its effects on HDL and triglycerides varied and ranged from -6.9% to
17.8%, and -46% up to an increase of 21%, respectively.

Table 1. Approximate Equivalent Daily Doses of Statins: LDL Lowering Data from Clinical Trials

Lovastati Simvastati Fluvastatin Pravastati Atorvastatin Rosuvastatin Pitavastati

n n n n

20 mg 10 mg 40 mg 20 mg -- -- 1 mg
40 mg 20 mg 80 mg 40 mg 10 mg -- 2 mg
80 mg 40 mg -- ** 20 mg -- 4 mg
-- 80 mg -- -- 40 mg 10 mg --
-- -- -- -- 80 mg 20 mg --

Efficacy (Plaque regression and outcomes studies)


One randomized open-label non-inferiority trial compared pitavastatin with atorvastatin to
determine the effects of LDL lowering on the regression of coronary plaque volume (PV) and
reduction of major adverse cardiac events (MACE). 4 A total of 307 patients with acute
coronary syndrome (ACS) and undergoing intravascular ultrasound (IVUS) were randomized
to either pitavastatin 4 mg or atorvastatin 20 mg for 52 weeks. Regression in PV was observed
with both pitavastatin and atorvastatin (pitavastatin -16.9% ± 13.9% versus atorvastatin
-18.1% ± 14.2%, p = 0.5) and differences in regression between statins did not exceed the
predefined non-inferiority margin of 5%. The incidence of MACE with pitavastatin was
20.4% compared to 22.8% with atorvastatin, which was not statistically different (p = 0.6).
There were no deaths reported in either arm of the trial.

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 Pitavastatin Monograph


Two other studies also evaluated the effect of pitavastatin on cardiovascular events. The first
was a multi-center study conducted in Korea in which 1,039 patients with an acute myocardial
infarction (AMI) were followed for one year. Although the study did not have a comparator
arm or control group, the incidence of MACE, all-cause mortality, and cardiac deaths at 52
weeks was 7.3%, 3.6%, and 2.1%, respectively. 5 In the second study, investigators
retrospectively compared the incidence of MACE between various doses of pitavastatin,
pravastatin, atorvastatin and placebo in 743 patients. There was a lower incidence of MACE
in patients taking pitavastatin versus the other statins (pitavastatin 8.3%, vs. atorvastatin
19.3%, vs. pravastatin 27.2% and placebo 35.1%) but the differences were not statistically
significant.6

Although there have been a few studies published, the effect of pitavastatin on MACE and in
patients with Fredrickson Type I, III and V dyslipidemias has yet to be adequately defined.

Safety
 Pitavastatin is generally well tolerated. In premarketing trials, the most common adverse
events included back pain (1.4-3.9%), gastrointestinal (GI) distress (1.5-3.6%), elevated
creatine phosphokinase (0.6%; CPK) and myalgia (0.5%) with the latter two generally
occurring more often with the highest dose. This is consistent with post-marketing data where
the most common side effects were creatine kinase elevations (1-6%; CK), dizziness (4%),
nasopharyngitis (5.4%), headache (3%) and GI upset (2%). Reports of myalgia and clinically
significant increases in liver function tests (LFTs) were noted to be as high as 4% and 7.4%,
respectively.1-7 Although the exact incidence is unknown, the most severe side effects of
pitavastatin include hypersensitivity reactions and rhabdomyolysis; similar to other statins.
 A two-year post-marketing surveillance study was conducted to examine the safety of
pitavastatin in clinical practice in Japan (n=19,925). 8 In that study, authors noted that
approximately 10.4% of patients experienced an adverse event which required discontinuation
in 7.4% of cases. The majority of adverse events were increases in CPK (2.74%), elevated
alanine aminotransferase (ALT) (1.79%) and myalgias (1.08%). Pitavastatin was generally
well tolerated in the elderly cohort since there were no differences in the rates of adverse
events between those greater than or younger than 65 years of age. There was only one
reported case of rhabdomyolysis in that study.
 There are limited safety data beyond 12-16 weeks comparing pitavastatin to placebo or to
comparator statins.
 In the FDA review of pitavastatin, the medical reviewer noted that significant differences in
safety and/or efficacy were not observed between pitavastatin and low to moderate dose
comparator statins.

Dosing
 The usual starting dose of pitavastatin is 2 mg once daily with or without food. The maximum
recommended dose is 4 mg daily due to a disproportionate increase in the risk for severe
myopathy with higher doses as demonstrated in premarketing clinical studies.
 For patients with moderate-severe renal impairment (glomerular filtration rate (GFR) less than
59 ml/min) or those taking rifampin, it is recommended to initiate pitavastatin at 1 mg daily
with the maximum recommended dose not to exceed 2 mg daily.
 When combined with erythromycin, the maximum recommended dose should not exceed 1
mg daily for pitavastatin.

Precautions/Contraindications
 Patients with a known hypersensitivity to any components of the formulation, those with
active liver disease or unexplained persistent elevations in their liver enzymes as well as
females who are pregnant/nursing or who are planning on becoming pregnant should avoid
using pitavastatin.
 As with all statins, patients should be instructed to report any unusual or unexplained muscle
tenderness, pain or weakness to their healthcare provider immediately.

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 Pitavastatin Monograph

 In patients with moderate-severe renal impairment (e.g. GFR less than 59 mL/min/1.73 m 2) or
those taking concomitant rifampin, the initial daily dose of pitavastatin should be 1 mg with
the maximum daily dose not to exceed 2 mg. The dose should be further limited to 1 mg daily
for those taking erythromycin due to the risk for myopathy.
 Co-administration of pitavastatin with cyclosporine is contraindicated.

Drug Interactions
 Pitavastatin is primarily metabolized by hepatic glucuronidation and to a minor extent by
cytochrome P450 (CYP) 2C9 and 2C8. Therefore, it is not subject to the many drug
interactions affecting CYP 3A4.
 Pitavastatin was shown to have no clinically significant effect on the systemic exposure of
warfarin. However, patients receiving the combination should continue to be monitored
closely for signs and symptoms of bleeding or elevations in warfarin exposure as evidenced
by an increase in prothrombin time (PT) or the international normalized ratio (INR).
 Since both rifampin and erythromycin can significantly increase the systemic exposure of
pitavastatin, lower maximum daily doses of pitavastatin are recommended when given
concomitantly with either drug.

Laboratory Monitoring
 The manufacturer recommends that patients have their liver function tests measured at
baseline and at 12 weeks following both initiation of therapy and dose escalation, and
periodically thereafter (e.g., semiannually).

In clinical trials examining pitavastatin’s effect on lipids, 2 mg of pitavastatin was non-inferior to

atorvastatin 10 mg and simvastatin 20 mg daily in reducing LDL and its effect on other lipid parameters.
The maximum daily dose of pitavastatin (4 mg) is approximately equivalent to simvastatin 40 mg and
atorvastatin 20 mg in reducing LDL from baseline. With regard to reducing adverse cardiovascular events,
pitavastatin, administered in an open-label fashion for one year (n=307), reduced plaque volume similar to
atorvastatin (as assessed by IVUS) in Japanese patients presenting with ACS. In the same study, the
incidence of major adverse cardiovascular events occurred at a similar rate in patients receiving either
atorvastatin or pitavastatin. At this time, there are no published, large, long-term, controlled studies
examining the effect of pitavastatin on cardiovascular events. However, there are at least two ongoing,
unblinded studies46-47 examining the effect of pitavastatin on cardiovascular outcomes: 1) comparing 1 mg
to 4 mg of pitavastatin in Japanese individuals with stable coronary artery disease 46, 2) comparing 2 mg vs.
4 mg of pitavastatin in Korean patients after a myocardial infarction. 47 Because of the lack of evidence to
support an effect on cardiovascular outcomes and the limited safety data in non-Asian populations
compared to the other available statins, pitavastatin should have limited use in VA.
Introduction35-37

Coronary heart disease (CHD) continues to be a significant cause of morbidity and mortality among
Americans. In 2006, CHD was responsible for over 420,000 deaths which is approximately 1 out of every 6
persons in the United States. 35 Elevated cholesterol, or hypercholesterolemia, is an important risk factor for
CHD. The 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors, also known as statins,
are an important component of care in the management of hypercholesterolemia because of their
effectiveness in reducing LDL, their safety and tolerability, and their demonstrated ability to reduce
cardiovascular morbidity and mortality in clinical trials. The statins work by blocking the HMG-CoA
reductase enzyme. This enzyme is the rate-limiting step in cholesterol synthesis and therefore by blocking
HMG-CoA reductase, statins reduce cholesterol production. As a result of the decreased cholesterol, a
greater number of LDL receptors are created which increases the uptake of LDL. The overall effect is
decreased LDL, total cholesterol (TC), and triglycerides (TG) and a slight increase in high-density
lipoprotein cholesterol (HDL).
Pitavastatin (Livalo®) was approved by the Food and Drug Administration (FDA) in August 2009 and is
the latest statin to be evaluated for inclusion on the VA National Formulary.

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 Pitavastatin Monograph

The purposes of this monograph are to (1) evaluate the available evidence regarding the safety, tolerability,
efficacy, cost, and other pharmaceutical issues of pitavastatin for possible addition to the VA National
Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA.

Pharmacology/Pharmacokinetics1-2,38
Pitavastatin works similar to other statins by inhibiting HMG-CoA reductase to reduce LDL, TC, and TG
and to increase HDL. Pitavastatin reaches peak plasma concentration (C max) approximately one hour after
oral administration with plasma levels increasing proportional to the dose. Taking pitavastatin with a high-
fat meal decreases the Cmax by 43%, however, the area-under-the-curve (AUC) concentration remains
relatively unchanged. The Cmax and the AUC concentration remain the same whether pitavastatin is taken in
the morning or evening. Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin
and alpha1-acid glycoprotein. Pitavastatin is primarily metabolized via hepatic glucuronidation (via
UGT1A3 and UGT2B7 forming the major metabolite, pitavastatin lactone) with minimal CYP 2C9 and
2C8 metabolism. The mean elimination half-life of pitavastatin is 12 hours. About 15% of the dose is
excreted in the urine.

Plasma concentrations of pitavastatin were determined after administration of a 2 mg dose in patients with
liver cirrhosis (Child-Pugh grade A and B). 1,38 In patients with Child-Pugh Grade A and B, the
administration of a 2 mg dose resulted in a 1.19- and 2.47-fold increase in C max and 1.27- and 3.64-fold
increase in AUC, respectively as compared with normal subjects. In contrast to the prescribing information,
the ratio of pitavastatin C max and AUC between patients with Child-Pugh A and B and healthy volunteers
was 1.3 (Child-Pugh A, Cmax) and 1.6 (Child-Pugh A, AUC) versus 2.7 (Child Pugh B, Cmax) and 3.8 (Child-
Pugh B, AUC), respectively. The mean half-life for mild or moderate hepatic impairment and healthy
volunteers was 15, 10, and 8 hours, respectively.
Table 2. Pharmacokinetic Properties of Statins1, 39-44
Atorvastati Fluvastati Lovastati Pravastati Rosuvastati Simvastati Pitavastati
n n n n n n n
Bioavailabilit
14% 24% <5% 17% 20% <5% 51%
y
Mean Half-
14-21 <2* 3-4 1.8 19 3 12
life (hours)
Excretion:
Renal <2% 5% 10% 20% 10% 13% 15%
Feces 98% 90% 83% 70% 90% 60% 79%
Metabolic CYP2C9, CYP2C9,
CYP3A4 CYP2C9 CYP3A4 Sulfation CYP3A4
Enzymes 2C19 2C8
Hepatic first
20-30% 40-70% 40-70% 50-70% Unknown 50-80% Unknown
pass effect
Lipophilicity Lipophilic Hydrophilic Lipophilic Hydrophilic Hydrophilic Lipophilic Lipophilic
*Fluvastatin XL t½ is 3-6 hours depending upon fed or fasted state.

FDA Approved Indication(s)

As an adjunct to diet and other non-pharmacologic measures to reduce elevated TC, LDL, apolipoprotein B
(ApoB, a component of LDL), TG levels and to increase HDL in adults with primary hyperlipidemia or
mixed dyslipidemia.

Potential Off-label Use

This section is not intended to promote any off-label uses. Off-label use should be evidence-based. See VA
PBM-MAP and Center for Medication Safety’s Guidance on “Off-label” Prescribing (available on the VA
PBM Intranet site only).

For the regression of coronary atherosclerosis in patients with acute coronary syndrome and for primary
and secondary prevention of major adverse cardiac events.

Current VA National Formulary Alternatives9

1) Simvastatin

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 Pitavastatin Monograph

2) Pravastatin
3) Lovastatin
4) Rosuvastatin*
5) Atorvastatin*
6) Fluvastatin*
*Nonformulary statins (Statin Criteria for Use are available on the PBM website)
Table 3. Approximate Statin Dose Equivalence9

Approximate Equivalent Daily Doses of Statins: LDL Lowering Data from Clinical Trials

Lovastati Simvastati Fluvastatin Pravastati Atorvastatin Rosuvastatin Pitavastati

n n n n

20 mg 10 mg 40 mg 20 mg -- -- 1 mg
40 mg 20 mg 80 mg 40 mg 10 mg -- 2 mg
80 mg 40 mg -- ** 20 mg -- 4 mg
-- 80 mg -- -- 40 mg 10 mg --
-- -- -- -- 80 mg 20 mg --
**If a patient is receiving Fluvastatin XL 80 mg daily, conversion to pravastatin 80 mg daily can produce similar reductions in LDL
(At 4 weeks, mean change in LDL was 37% for pravastatin 80 mg vs. median LDL change of 38% for fluvastatin XL 80 mg). 9
Immediate release fluvastatin should be used only in doses of 20 or 40 mg daily. In those patients requiring 80 mg daily, conversion to
fluvastatin XL is recommended.

Table 4. Formulary Considerations for Current Statins9

Formulary Status

Lovastati Simvastati Fluvastatin Pravastati Atorvastatin Rosuvastatin Pitavastati

n n n n

Formulary or Formular Non- Non- Non- Undergoin

Formulary Formulary
Non-Formulary y formulary formulary formulary g Review
Criteria for Criteria for Criteria for Criteria for
NF Use: Can Use: For NF Use: For NF Use: For
consider fluva those on patients with patients not
in those potent CYP an meeting their
patients 3A4 inadequate LDL goals on
receiving inhibitors. LDL lowering simvastatin
cyclosporine response to 40 mg daily or
or gemfibrozil, simvastatin with
as fluvastatin 40 mg daily or maximally
Recommendation
concentration maximally tolerated or
s For Use
s are less tolerated or recommende
affected when recommende d doses of
combined d doses of pravastatin
with these pravastatin and receiving
agents. and not potent CYP
receiving 3A4
potent CYP inhibitors.
3A4 Initial dose 5
inhibitors. mg daily.

Dosage and Administration

The usual starting dose of pitavastatin is 2 mg daily with a dosing range of 1-4 mg daily. The initial dose
and dose adjustments should be individualized according to patient characteristics including comorbidities,
LDL goal, concomitant medications and response measured after at least 4 weeks. The maximum
recommended dose is 4 mg daily due to an increased of severe myopathy at higher doses.

In patients with moderate to severe renal impairment (GFR 15-59 ml/min), those taking concomitant
rifampin or with end-stage renal disease on hemodialysis, the initial and maximum recommended doses are
1 and 2 mg once daily, respectively.

Patients taking concomitant erythromycin should not be taking more than 1 mg of pitavastatin daily.
Co-administration of pitavastatin with cyclosporine is contraindicated.

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 Pitavastatin Monograph

Pitavastatin may be administered with or without food as the LDL lowering effects of pitavastatin are not
significantly affected by meals. Pitavastatin may also be given at any time during the day although there is
a slightly greater reduction in LDL after evening dosing.

Table 5. Pitavastatin Dosing Adjustments1

Circumstance Starting Dose Maximum Dose
Moderate Renal Impairment (GFR 30-59
1 mg daily 2 mg daily
mL/min/1.73 m2)
Severe Renal Impairment (GFR 15-29
1 mg daily 2 mg daily
mL/min/1.73 m2), with or without dialysis
Concomitant erythromycin -- 1 mg daily
Concomitant rifampin 1 mg daily 2 mg daily

Efficacy1-34
Efficacy Measures: Pitavastatin was approved based upon its ability to reduce LDL cholesterol in
comparison to other statins as demonstrated in non-inferiority trials. For the statin class, reductions in LDL
have correlated with reductions in cardiovascular events.
1. Lipids:
a. % LDL, TC, ApoB, ApoA1, non-HDL, TG lowering from baseline, and % increase in
HDL from baseline.
b. Percentage of patients meeting National Cholesterol Education Panel (NCEP) Adult
Treatment Panel-3 (ATP 3).
2. Atherosclerotic Plaques (regression):
a. Intravascular Ultrasound (IVUS) - Regression in plaque volume (PV) of the target
coronary vessel in the setting of ACS as detected by IVUS-guided percutaneous coronary
intervention (PCI)
i. [PV (follow-up) – (baseline)/PV (baseline)] x 100
ii. Coronary plaque volume is calculated as the sum of the difference between the
external elastic membrane and lumen area.
iii. Follow-up was at 8-12 months after enrollment or baseline.
3. Cardiovascular outcomes: All-cause mortality, cardiac-related mortality, nonfatal MI, Target
Lesion Revascularization (TLR), and Target Vessel Revascularization (TVR).

Summary of Efficacy Findings:

To date, there have been 4 studies (3 OL vs. 1 DB) comparing the mean LDL lowering effectiveness of
pitavastatin to placebo, 14 (10 OL vs. 3 DB vs. 1 PROBE) to atorvastatin, 3(1 OL vs. 2 DB) to simvastatin,
3 (1 OL vs. 2 DB) to pravastatin, and 1 (OL) for each to rosuvastatin and fenofibrate. The trials were
mostly randomized open-label active comparator trials lasting 12 weeks in duration but ranging from 8
weeks to 7 years and primarily enrolling less than 100 patients with only 2 enrolling more than 1,000
subjects. These studies generally focused on changes from baseline in LDL, HDL, non-HDL, TG and
ApoB levels expressed as either a percentage or absolute value. Pitavastatin was shown to reduce LDL,
Total Cholesterol (TC), non-HDL cholesterol and Apolipoprotein B (ApoB) by 26.2-48%, 16.6-37%, 22.5-
45%, and 17.4-41%, respectively. However, its effects on HDL and triglycerides varied and ranged from
-6.9% to 17.8%, and -46% to 21%, correspondingly.

In terms of regression in coronary plaque volume using IVUS, one study found a reduction of 16.9% with
pitavastatin 4 mg compared to 18.1% (p = 0.5) with atorvastatin 20 mg. 4 However, these changes in PV
differed remarkably from another study which showed a reduction of only 2.6% with pitavastatin 2 mg as
compared to an increase of 0.2% with atorvastatin 10 mg (p = 0.107).25

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 Pitavastatin Monograph

There were three trials that evaluated the incidence of major adverse cardiac events in patients receiving
pitavastatin.4-6 One was a prospective, randomized, open-label, blinded endpoint trial that compared
pitavastatin 4 mg with atorvastatin 20 mg and found a numerical but non-statistically significant decrease in
the composite of MI, coronary revascularization, TLR, TVR, other revascularization and all-cause
mortality (20.4% vs. 22.8%, respectively; p = 0.6). 4 There was a second open-label trial that retrospectively
examined the incidence of cardiovascular events (e.g. all-cause mortality, sudden cardiac death, fatal MI,
nonfatal MI, TLR, etc) between various doses of atorvastatin, pitavastatin, pravastatin and a non-statin
group.5 In terms of the total number of events, pitavastatin was associated with the lowest number of events
(8.3%) as compared to atorvastatin (19.3%), pravastatin (27.2%) and no-statin (35.1%), but the differences
were not statistically significant. The last was an open label study that reported the incidence of major
adverse cardiac events with pitavastatin 4 mg in 1,039 patients over 52 weeks but did not have a
comparator or control group.6 In this study, the rate of composite events, which included all-cause
mortality, cardiac deaths, recurrent MI, TLR and TVR, was approximately 7.3% at 52 weeks.

Table 6. Summary of Efficacy Measures/Findings from Clinical Trials1-34

# of Compariso Duration
Reference Design Efficacy in Cholesterol Lowering and Additional Comments
Patients n (mg) (weeks)
Δ in TC%, LDL, HDL, non-HDL, TG, ApoB:
2 mg: -28%, -38%, 4%, -35%, -14%, -30%
Pitava 2-4 vs.
N = 817 12 4 mg: -32%, -45%, 5%, -41%, -19%, -35%
Atorva 10-20
10 mg: -28%, -38%, 3%, -35%, -18%, -29%
20 mg: -33%, -44%, 2%, -41%, -22%, -36%
Δ in TC%, LDL, HDL, non-HDL, TG, ApoB:
2 mg: -28%, -39%, 6%, -36%, -16%, -30%
Pitava 2-4 vs.
N = 843 12 4 mg:-32%, -44%, 6%, -36%, -17%, -35%
Simva 20-40
20 mg: -25%, -35%, 6%, -41%, -16%, -27%
40 mg: -31%, -43%, 7%, -39%, -16%, -34%
Δ in TC%, LDL, HDL, non-HDL, TG, ApoB:
1 mg: -22%, -31%, 1%, -29%, -13%, -25%
2 mg: -27%, -39%, 2%, -36%, -15%, -31%
Pitava 1-4 vs.
Product R, DB, N = 942 12 4 mg: -31%, -44%, 4%, -41%, -22%, -37%
Prava 10-40
Information AC, NI 10 mg: -15%, -22%, 0%,-20%, -5%, -17%
20 mg: -21%, -29%, -1%, -27%, -11%, -22%
40 mg: -24%, -34%, 1%, -32%, -15%, -28%
Δ in TC%, LDL, HDL, non-HDL, TG, ApoB:
Pitava 4 vs.
N = 351 12 4 mg: -31% - 44%, 7%, -41%, -20%, -34%
Simva 40
40 mg: -31%, -44%, 5%, -39%, -15%, -34%
Δ in TC%, LDL, HDL, non-HDL, TG, ApoB:
Pitava 4 vs.
N = 410 12 4 mg: -28%, -41%, 7%, -36%, -20%, -32%
Atorva 20
20 mg: -32%, -43%, 8%, -40%, -27%, -34%
Δ in TC%, LDL, HDL, TG, ApoB:
Pcb: -2%, -3%, 0%, 1%, -2%
R, DB, Pitava 1-4 vs.
N = 251 12 1 mg: -23%, -32%, 8%, -15%, -25%
PC Pcb
2 mg: -26%, -36%, 7%, -19%, -30%
4 mg: -31%, -43%, 5%, -18%, -35%
Primary Endpoint: % Δ in TC, LDL, HDL, non-HDL, TG, ApoA1, ApoB
Kajinami Δ in TC%, LDL, HDL, non-HDL, TG, ApoA1, ApoB:
OL N = 30 Pitava 2-4 16
(2000) 2 mg, -31%, -40%, -1.9%, -36%, -15%, 9.5%, -34%
4 mg, -37%, -48%, 1.9%, -45%, -23%, 0%, -41%
Primary Endpoint: % Δ in TC, LDL, HDL. TG, ApoA1, ApoB
Δ in TC%, LDL, HDL. TG, ApoA1, ApoB:
Noji (2002) OL N = 25 Pitava 2-4 104
2 mg, -31%, -41%, 5%, 0%, 13%, -33%
4 mg, -33%, -44%, 6%, 9%, 12%, -34%
Primary Endpoint: Avg. % Δ in TC, LDL, TG from baseline
Δ in TC%, LDL, TG, pts. achieving NCEP goal::
2 mg, -28.2%, -37.6%, -14.1%, 75%
N = 236,
R, DB, Pitava 2 vs. 10mg, -14%, -18.4%, -5%, 36%
Saito (2002) 240 12
AC Prava 10 All values stat. signif from baseline between groups. 2.4% and 1.8% of pts. taking pitava
enrolled
and prava withdrew due to mild-moderate AEs. 4% and 2% had drug-related ↑CK
elevations but none with symptoms. >3x ULN for ALT in 2 pts. with pitava and 1 for
prava.
Primary Endpoint: % Δ in LDL, HDL, TG, FPG, HgbA1c
Δ in LDL%, HDL, TG, FPG, HgbA1c:
Kawai (2005) OL N = 79 Pitava 1-2 8
1-2 mg: 37%, 3%, -9.9%, 0.8%, 0.02%
Diabetic study population. Only changes in LDL and TG were stat. signif. (p < 0.0001).
Park (2005) R, OL, N = 95, Pitava 2 vs. 8 Primary Endpoint: Avg. % Δ LDL from baseline
AC 104 Simva 20 Secondary Endpoints: Avg. % Δ in TC, TG, and HDL from baseline, pts achieving
enrolled NCEP goal
Δ in TC% LDL, HDL, TG, pts. achieving NCEP Goal:
2 mg: -26.9%, -38.2%, 8.3%, -29.8%, 93.9%
20 mg: -28.5%, -39.4%, 3.6%, -17.4%, 91.3%

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 Pitavastatin Monograph

62% of pop. female. Results not stat. signif. At least 25% and 11.5% had 1 AE while
37.3% and 23.5% had an ADR* for pitava and simva. Common AEs are ↑CK 2x ULN in
3.8% for pitava vs. 9.8% simva.
Primary Endpoint: Δ in TC%, LDL, HDL, TG
Δ in TC%, LDL, HDL, TG:
Yoshitomi Pitava 1 vs.
OL N = 137 12 1 mg: -28%, -38%, 3%, -11%
(2006) Atorva 10
10 mg: -29%, -41%, 7%, -21%
Changes stat. signif. compared to baseline. No AEs were reported in either arm.
Primary Endpoint: Proportion of pts. achieving NCEP LDL goal
Secondary Endpoints: % Δ in LDL, TC, TG, HDL and hs-CRP from baseline
Δ in TC%, LDL, HDL, TG, pts. reaching NCEP LDL goal:
2 mg: -28.2%, -42.9%, 7.1%, -9.9%, 92.7%
N = 222;
R, OL, Pitava 2 vs. 10 mg: -29.6%, -44.1%, 6.7%, -11%, 92%
Lee (2007) 268 8
AC Atorva 10 67% of study pop. Female. Values not stat. signif. 19.1% pitava with AEs vs. 25%
enrolled
atorva. ↑CK (4.4%) most common but no serious AEs. No myopathy (CK>10x ULN
with muscle symptoms) in either group. One pt in the pitava and 2 pts in the atorva had
an ALT>2x the
ULN after 8 wks.
Primary Endpoint: Δ in sd-LDL in patients with type 2 diabetes
Secondary Endpoints: Δ % in LDL, HDL, TG, ApoA1, ApoB, FPG%, HgbA1c
Pitava 1 vs. Δ in LDL%, HDL, TG, ApoA1, ApoB, FPG%, HgbA1c:
Tokuno
OL N = 72 Micronized 12 1 mg: -46%, 1%, -46%, 7%, -31%, 12%, 0%
(2007)
Fenofibrate 100 100 mg: -3%, 6%, -173%, 7%,-15%,-19%, 0%
All values not stat. signif. except LDL, TG, ApoA1/B for Pitava and TG, HDL, ApoB
for Fenofibrate. CK and LFTs reported as “essentially unchanged” but data not shown.
Primary Endpoint: % Δ in LDL, HDL, TG, hsCRP
Koshiyama Δ in LDL%, HDL, TG, hsCRP:
OL N = 178 Pitava 1-2 52
(2008) 1-2 mg: -30.3%, 2.6%, -15.9%, -34.8%
No serious AEs observed including Δ in HgbA1c.
Primary Endpoint: Δ in sd-LDL and RLP in familial hypercholesterolemia
Secondary Endpoint: % Δ in TC, HDL, TG, hsCRP
R, OL, Pitava 2 vs. Δ in TC%, LDL, HDL, TG, ApoAI, ApoB, hsCRP:
Nozue (2008) N = 17 12
AC Atorva 10 2 mg: -31.5%, -44.8%, -6.9%, 5.5%, 10.9%, -36.9%, -26.3%
10 mg: -27.7%, -39.3%, -1.6%, -17%, 11.1%, -32.9%, -33.3%
Only TC, LDL and Apo-B values stat. signif.
Primary Endpoint: Effects on lipid profile, fibrinolytic parameter and endothelial
function
Δ (after 3 months) in TC%, LDL, HDL, TG, PAI-1 (ng/mL), FMD%, NTG-D%,
Pitava 2 vs.
Sakabe (2008) R, OL N = 71 12 mean BP (mm Hg):
Atorva 10
2 mg: -26%, -43.2%, 0%, -7.3%, -4, 5.5%, -0.3%, -2
10 mg: -33.7%, -44.6%, -1.8%, -8.5%, -11, 3.7%, -0.2%, -2
TC and HDL stat. signif.
Primary Endpoint: Different in % Δ in serum HDL
Secondary Endpoints: %Δ in LDL, non-HDL, LDL/HDL ratio, TG, ApoA1, ApoB,
ApoB/AI ratio, ApoE
Δ in LDL%, HDL, non-HDL, ApoAI ApoB, ApoE:
N = 173;
R, OL, Pitava 2 vs. 2 mg: -40.1%, 8.2%, -37.4%, 5.1%, -35.1%, -28.1%
Sasaki (2008) 207 52
AC Atorva 10 10 mg: -33%, 2.9%, -31.1%, 0.6%, -28.2%, -17.8%
enrolled
All values statistically significant from baseline and between groups. Women accounted
for 62% of study pop. AE were 9% pitava and14% atorva. No patients had an AST >3x
ULN, CK>10x ULN, or Cr>1.5x ULN. 2pts. with pitava and 0 with atorva had an ALT
value >3x ULN (P = NS).
Primary Endpoint: % Δ in non-HDL from baseline
Secondary Endpoints: % Δ in TC, LDL, TG, HDL
Δ in TC%, LDL, HDL, non-HDL, TG:
R, OL, Pitava 2 vs.
Yokote (2008) N = 204 12 2 mg: -29.7%, -42.6%, 3.2%, -39%, -17.3%
AC Atorva 10
10 mg: -31.1%, -44.1%, 1.7%, -40.3%, -10.7%
Primary endpoint of non-HDL not stat. signif..
Both treatment arms very well tolerated with no stat. signif. ↑ in CK or LFTs for Pitava.
Primary Endpoint: % Δ in coronary PV
Secondary Endpoints: Nominal changes in % PV and normalized PV
Δ in TC%, LDL, HDL, non-HDL, TG, ApoA1 ApoB, hsCRP, HgbA1c%, PV:
4 mg: -21.6%, -36.2%, 9.9%, -30.5%, 16.2%, 18.5%, -27.6%, -97.3%, 0.6%, -16.9%
20 mg: -21.9%, -36.8%, 8%, -30.1%, 21.2%, 14%, -27.6%, -95.4%, 0.6%, -18.1%
MACE (%), MI, Coronary Revasc, TLR, TVR, Other Revasc, All-Cause Mortality
Pitava 4 vs.
Hiro (2009) PROBE N = 307 52 4 mg: 20.4%, 0%, 20.4%, 10.9%, 6.1%, 5.4%, 0%
Atorva 20
20 m: 22.8%, 2%, 20.8%, 12.8%, 5.4%, 6%, 0%
Above lab values stat. signif. from baseline but not between groups with the exception of
PV. All MACE not stat. signif. 2.7% discontinued pitava vs. 4.7% atorva. ↑AST/ALT
was 7.5% with pitava vs. 7.4% for atorva (p = 0.97) and 5.4% for both groups (p =
0.98), respectively. There were 3 cases in each group with LFTs greater than 100 IU/L
and 1 case in each group of LFTs greater than 350 IU/L.
Primary Endpoint: % Δ in LDL, HDL, TC, TG, HgbA1c%, CAVI
Miyashita
R, OL N = 45 Pitava 2 52 Δ in LDL%, HDL, TC, TG, HgbA1c%, CAVI:
(2009)
2 mg: -39 mg/dL, 5.4 mg/dL, -43 mg/dL, -6 mg/dL, -0.2%, -0.63 mg/dL
Primary Endpoint: Δ in TG, HDL, hsCRP
Motomura Secondary Endpoint: % Δ in TC, LDL, HgbA1c, FPG
OL N = 65 Pitava 2 26
(2009) Δ in TC%, LDL, HDL, TG, hsCRP, HgbA1c, FPG:
2 mg: -27.2%, -41.8%, 3.4%, -11.6%, -24.5%, 4.4%, 1.5%

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 Pitavastatin Monograph

Stat. signif. for all values except FPG. Baseline hs-CRP level ~ 0.49 mg/L.
Primary Endpoint: Changes in coronary lesions (e.g. PV, fibrofatty volume index)
Secondary Endpoint: % Δ in TC, LDL, HDL, TG
Pitava 2 vs. Δ in TC%, LDL, HDL, TG, PVI:
Toi (2009) R, AC N = 160 3
Atorva 10 2 mg: -22.5%, -31%, -2.6%, -8%, -2.6%
10 mg: -22%, -27.9%, -5.1%, 0.8%, 0.2%
Results not stat. signif. No serious CV events in either group.
Primary Endpoint: % Δ in TC, LDL, HDL, non-HDL, ApoA1, ApoB
Δ in TC%, LDL, HDL, non-HDL, ApoA1, ApoB
Fukutomi
OL N = 43 Pitava 1-2 52 1-2 mg: -16.6%, -28.5%, 13.6%, -22.5%, 10.7%, -17.4%
(2010)
Two unspecified ADRs observed (4.7%) with only one requiring
discontinuation.
Primary Endpoint: Δ in coronary PV after 52 wks
Secondary Endpoint after 52 wks: % Δ in TC, LDL, HDL, ApoA1 ApoB, TG
Δ in PV%, TC, LDL, HDL, ApoA1 ApoB, TG:
Kodama
OL N = 90 Pitava 2 52 2 mg: -0.1%, -22.3%, -34.5%, 17.8%, 15.5%, -28.9%, -12.8%
(2010)
All values stat. signif. except ΔPV.
15.6% experienced AEs with 2 reports of each hypertension and ↑GGT as the most
commonly reported.
Primary Endpoint: Changes in serum lipids and its association on CV events
Changes in LDL-C%, HDL:
Pitava: -34.2%, 13.4%
Atorva: -32.8%, 7.0%
Prava: -23.7%, 5.4%
Pcb: -1.8%, 5.3%
Pitava vs
Maruyama Cardiovascular Events% (Total, SCD, Fatal MI, Nonfatal MI, TLR):
OL N = 743 Atorva vs Prava 364
(2010) Pitava: 8.3%, 0.6%, 0%, 0%, 3.3%
vs Pcb
Atorva: 19.3%, 0%, 0%, 0%, 7.5%
Prava: 27.2%, 0%, 0%, 0.7%, 12.6%
Pcb: 35.1%, 2%, 0.4%, 1.2%, 14.7%
Retrospective study. Doses unavailable. Not all values stat. signif. When baseline HDL
stratified between < 45mg/dl and >45mg/dl, only pitava significantly increased HDL in
patients with a baseline of < 45mg/dl
Primary Endpoint: Safety and tolerability of pitavastatin 4 mg once daily
Secondary Endpoints: Effect on lipid/lipoprotein fractions and ratios and LDL
attainment
Δ in TC%, LDL, HDL, non-HDL, TG, ApoB, ApoA1, hsCRP, pts. reaching NCEP
goal:
Ose (2010) R, OL N = 1353 Pitava 4 52
4 mg: -29.6%, -42.9%, 14.3%, -39.6%, -17.5%, -36.25%, 2.4%, -0.2, 74%
4.1% withdrew due to AEs but none were serious. The incidence of: ↑CPK (5.8%),
nasopharyngitis (5.4%) and myalgia (4.1%) were most common with no reports of
myopathy/myositis/rhabdo or
↑ LFTs.
Primary Endpoint: % Δ in LDL, TC, proportion of pts. reaching LDL goal
Sansanayudh R, OL, Pitava 1 vs. Δ in LDL%, TC, proportion of pts. reaching LDL goal:
N = 98 8
(2010) AC Atorva 10 1 mg: -37% -28%, 74%
10 mg: -46%, -32%, 84%
Primary Endpoint: hsCRP level at 52 weeks
Yoshika
PC N = 30 Pitava 2 vs. Pcb 52 hsCRP level at 52 weeks:
(2010)
Absolute values similar between groups at 52 weeks
Primary Endpoint: Δ in LDL in patients with type 2 DM and combined
dyslipidemia
Changes in LDL and FBGin patients with type 2 DM and combined dyslipidemia
Pitava: 41%, 2.1%
Gumprecht R, DB, Pitava 4 vs. 12 (Ext.
N = 399 Atorva: 43%, 7.1%
(2011) AC, NI Atorva 20 Study 44)
Extension Study: Safety and tolerability: BG and LDL target achievement
Pitava: 49.7%, 3.5%, -41%
Atorva: 46.5%, 7.3%, -41.4%
All values not statistically significant.
Primary Endpoint: All-cause mortality at 12 months after index PCI
Secondary Endpoints: All other individual. hard end points and cumulative MACE at
12 months
Δ in TC%, LDL, HDL, TG, hsCRP:
4 mg: -17%, -26.2%, -2.2%, 21%, -77%
Suh (2011) OL N = 1039 Pitava 4 mg 52 Total MACE%, All-cause mortality, Cardiac Deaths, Recurrent MI, TLR, TVR:
4 mg: 7.3%, 3.6%, 2.1%, 1.6%, 4.7%, 6.5%
Overall 318 (30.6%) AEs in 220 pts. (21.2%) reported. 15 AEs (4.7%) related to
pitavastatin and 5 (1.6%) were probably related to pitava tx. 11 events caused a hold of
pitava tx and 32 events ended in withdrawal. Mean CPK and LFTs normalized during 1st
month and remained stable throughout 12 months. No control group
Saku (2011) R, AC, N = 302 Pitava 2 vs. 16 Primary Endpoint: Rate of drug-related adverse events; Δ in LDL
NI Atorva 10 vs. Secondary Endpoints: The incidence of ADRs.
Rosuva 2.5 Δ in modified LDL%, HDL, TG, pts. reaching JAS LDL goal:
2 mg: -40%, 0, -25%, 95%
10 mg: -41%. 0, -28%, 94%
2.5 mg: -40%, 3, -30%, 89%
Lipid changes from baseline (NS) between groups. Drug related AEs requiring
discontinuation: 8.1% pitava, 4% rosuva, and 5.1% atorva (NS). No difference in ADEs
or laboratory ADEs (CK, LFTs, etc.) between groups except higher rate of ALT

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 Pitavastatin Monograph

elevation with atorva vs. other statins (p=0.043). But, unclear whether changes were
clinically important.
Primary Endpoint: Evaluate factors that change the protective action of statins on
cardiorenal function
Secondary Endpoint: % Δ in TC, LDL, HDL, non-HDL, TG
Yagi (2011) PC N = 105 Pitava 1 vs. Pcb 16 Δ in TC%, LDL, HDL, non-HDL, TG, E/e’, Parameter of LVDF and Albuminuria
(mg/g):
1 mg: -21.5%, -31.6%, 0%, -28.7%, -10.9%, 6.3, 19.1
All values stat. signif.
Key: AC = Active Control; DB = Double Blind; NI = Non-Inferior; R = Randomized; PC = Placebo Controlled; OL = Open Label; PROBE =
Prospective, Randomized, Open-Label, Blinded Endpoint; CV = Cardiovascular; GGT = gamma glutamyl transpeptidase; AE = Adverse Events; ADR =
Adverse Drug Reaction; HDL = High-Density Lipoprotein Cholesterol; FPG = Fasting Plasma Glucose; LDL = Low-Density Lipoprotein Cholesterol; sd
- LDL = small dense Low-Density Lipoprotein Cholesterol; TC = Total Cholesterol; PV = Plaque Volume; TG = Triglycerides; ApoA1 = Apolipoprotein
A1; ApoB = Apolipoprotein B; SCD = Sudden Cardiac Death; CPK = Creatine Phosphokinase; LFTs = Liver Function Tests; MACE = Major Adverse
Cardiac Events; SCD = Sudden Cardiac Death; MI = Myocardial Infarction; TLR = Target Lesion Revascularization; TVR = Target Vessel
Revascularization; Other Revasc. = Other Revascularization; PAI-1 = Plasminogen Activator Inhibitor Type 1; FMD = Flow-Mediated Vasodilation;
NTG-D = Nitroglycerin Induced Vasodilation; BP = Blood Pressure; E/e’ = Ratio of peak transmitral flow velocities of E/A and the ratio of peak E
velocity to early disastolic mitral annulus velocity; LVDF = Left Ventricular Diastolic Function; CAVI = Cardioankle vascular index; HgbA1c =
Hemoglobin A1C; hsCRP = high sensitivity C-Reactive Protein; NCEP = National Cholesterol Education Panel; *Adverse events (AEs) determined to be
highly probable, probable, possible, and unknown as opposed to unlikely were categorized as related to the study medication and referred to as adverse
drug reactions (ADRs); pts. = Patients; wks = weeks; JAS = Japanese Atherosclerosis Society; Stat. Signif. = Statistically Significant, ULN = Upper
Limits of Normal

Adverse Events (Safety Data)

Deaths and Other Serious Adverse Events
Serious adverse events with pitavastatin may include myopathy and rhabdomyolysis which can
subsequently lead to acute renal failure and death.
Common Adverse Events
In premarketing trials, there were approximately 3,291 patients who received doses of pitavastatin
ranging from 1-4 mg daily. The average trial duration was almost 37 weeks with the majority of
patients being female (52%) and Caucasian (93%) with an average age of 61 years old. The most
common adverse reactions are reported in Table 7 below. Approximately 3.9%, 3.3%, and 3.7% of
patients who were taking pitavastatin 1, 2, and 4 mg discontinued treatment due to adverse reactions.

Table 7: Adverse Reactions Reported in the Prescribing Information1

Adverse Placebo Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg
Reactions (n = 208) (n = 309) (n = 951) (n = 1540)
Back Pain 2.9% 3.9% 1.8% 1.4%
Constipation 1.9% 3.6% 1.5% 2.2%
Diarrhea 1.9% 2.6% 1.5% 1.9%
Myalgia 1.4% 1.9% 2.8% 3.1%
Pain in
1.9% 2.3% 0.6% 0.9%
Extremities

In post-marketing clinical trials, rates of discontinuation for pitavastatin ranged from 0-8.1% with the
most common side effects being CPK elevation (1-6%), dizziness (4%), nasopharyngitis (5.4%),
headache (3%) and GI upset (2%). Reported rates of increase in CK (>2xULN) and any increase in
LFTs were noted to be as high as 4% and 7.5%, respectively.2-8
A two-year post-marketing surveillance study was conducted to analyze the safety of pitavastatin (1-4
mg daily) in approximately 19,925 Japanese patients during routine clinical practice. 8 After 2 years of
follow-up, approximately 10.4% of patients experienced an adverse event which required
discontinuation in 7.4%. The majority of adverse events, however, were mild (84%) with only 1%
classified as severe. Increases in CPK were the most common adverse event (2.74%) followed by
elevated alanine aminotransferase (1.79%), aspartate aminotransferase (1.50%) and myalgias (1.08%).
The incidence of increased LFTs is similar to that of 0.2–2.3% reported with atorvastatin. 39 The most
frequent severe adverse drug events were abnormal liver function (4 events), liver disorder (3 events),
cataract operation (3 events), and AST/ALT increased (4 events). These adverse drug events generally
resulted in discontinuation of pitavastatin. There were no reported cases of liver transplant or deaths
due to pitavastatin. There was one reported case of rhabdomyolysis. Pitavastatin was generally well
tolerated in the elderly cohort since there were no differences in the rates of adverse events between
those greater than or younger than 65 years of age.

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 Pitavastatin Monograph

Contraindications
Pitavastatin is contraindicated in the following patient groups:
 Hypersensitivity to pitavastatin or any component of the formulation
 Pregnancy or those who may become pregnant
 Breastfeeding
o Pitavastatin is a pregnancy category X, although there are no adequate and well-
controlled studies of pitavastatin in pregnant women. Cholesterol and triglyceride
levels are elevated to a certain extent during pregnancy and required for fetal
development. Pitavastatin has been demonstrated in animal studies to pass into breast
milk. Since atherosclerosis is a progressive condition, temporary withdrawal of statin
therapy during pregnancy and nursing is expected to have little impact on the long-
term treatment outcome.
 Active liver disease or unexplained and persistent elevations in liver function tests
 Patients receiving cyclosporine. Concurrent administration of pitavastatin and cyclosporine
are contraindicated

Warnings and Precautions

As with all statins, patients should be instructed to report any unexplained muscle tenderness, pain or
weakness to their healthcare provider immediately. Patients who are older (over 65 years of age); have
concomitant renal impairment; or inadequately treated hypothyroidism are at an increased risk of
developing myopathy. Additionally, higher doses of pitavastatin, concomitant use of fibrates, lipid-
modifying doses of niacin or other clinically significant interacting drugs may further increase the risk
of myopathy and/or rhabdomyolysis. Pitavastatin should be used with extreme caution or temporarily
discontinued in situations where patients may develop an acute, serious condition suggestive of
myopathy or be predisposed to the development of renal failure secondary to rhabdomyolysis (e.g.
sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine and electrolyte
disorders; or uncontrolled seizures). Pitavastatin use should be discontinued if a patient develops
marked increases in CPK levels or if myopathy is suspected or diagnosed.

Pitavastatin should be used with caution in patients with known heavy alcohol use. Similar to other
statins, increased serum transaminase levels have been reported with pitavastatin use. In most cases,
transient elevations in LFTs may resolve or improve on their own or after a temporary interruption in
therapy. Liver enzymes should be monitored before initiation and after 12 weeks of statin therapy or
any escalation in dose and then periodically thereafter. If LFTs increase more than three times the
upper limit of normal at anytime during therapy then a reduction in dose or discontinuation is
recommended.

The safety and efficacy of pitavastatin in pediatric patients has not been established.

Sentinel Events
None. Refer to post-marketing data for information.

Look-alike / Sound-alike (LA/SA) Error Risk Potential

As part of a JCAHO standard, LA/SA names are assessed during the formulary selection of drugs. 
Based on clinical judgment and an evaluation of LA/SA information from four data sources (Lexi-
Comp, USP Online LA/SA Finder, First Databank, and ISMP Confused Drug Name List), the
following drug names may cause LA/SA confusion:

LA/SA for generic name: Pitavastatin

 Pravastatin
 Pentostatin

LA/SA for brand name: Livalo®

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 Pitavastatin Monograph

 Lipitor®
 Lovaza®

Laboratory Monitoring
As with other statins and according to the manufacturer’s recommendations, LFTs should be
monitored at baseline and 12 weeks after initiation or dose escalation of pitavastatin; then periodically
(e.g. every 6 months) thereafter. A fasting lipid profile should be performed prior to initiation of
therapy and at 6-8 weeks after initiation or dose escalation to evaluate efficacy. Baseline levels of CPK
are not necessary unless the patient is at risk for myopathy (e.g. renal or hepatic dysfunction;
concomitant drug interaction that inhibits statin metabolism, etc.). Routine monitoring of CPK is not
necessary unless patient becomes symptomatic (e.g. intolerable muscle symptoms).

Drug Interactions1,45
Drug-Drug Interactions
Pitavastatin is primarily metabolized via hepatic glucuronidation with minimal CYP 2C9 and 2C8
metabolism. Most of the dose is excreted in the feces; about 15% is excreted in the urine.

When pitavastatin was combined with cyclosporine, the AUC and C max of pitavastatin were increased
4.6- and 6.6-fold, respectively. As a result, the concomitant use of cyclosporine and pitavastatin is
contraindicated.

When pitavastatin was combined with erythromycin, the AUC and C max of pitavastatin were increased
2.8- and 3.6-fold, respectively. Therefore if co-administration is necessary, do not exceed 1 mg of
pitavastatin per day.

When pitavastatin was combined with gemfibrozil, the AUC and C max of pitavastatin were increased by
45% and 31%, respectively. When pitavastatin was combined with fenofibrate, the AUC and C max of
pitavastatin were increased 18% and 11%, respectively. Caution is advised when pitavastatin given
concomitantly with gemfibrozil or fenofibrate due to the increased risk of myopathy.

Although the combination of pitavastatin and lopinavir/ritonavir has not been studied, it is
recommended to avoid this combination due to the risk of increased pitavastatin exposure. This
recommendation is based on information known about the concomitant administration of
lopinavir/ritonavir with another HMG-CoA reductase inhibitor.

When pitavastatin was combined with rifampin, the AUC and C max of pitavastatin were increased 29%
and 2-fold, respectively. Therefore if concomitant use of pitavastatin and rifampin is necessary, do not
exceed 2 mg of pitavastatin per day.

The risk of skeletal muscle effects (e.g., myopathy and rhabdomyolysis) may be enhanced when
pitavastatin is used in combination with niacin. Therefore, a reduction in the pitavastatin dose should
be considered in this setting. Risk is increased in a dose-dependent manner, with advanced age (age
greater than 65), renal impairment, inadequately treated hypothyroidism, and concomitant use of
fibrates. Patients should be advised to report any unusual or unexplained muscle weakness, tenderness,
or pain.

There were no significant pharmacokinetic interactions with R- and S-warfarin. Pitavastatin has not
been shown to have a significant effect on prothrombin time (PT) or international normalized ratio
(INR) when administered to patients receiving chronic warfarin treatment. However, it is
recommended that patients be monitored when receiving the combination.
Table 8. Effect of Concomitant Medications on Pitavastatin Systemic Exposure1,45
Concomitant Change in Change in
Dose Regimen
Drug Pitavastatin AUC Pitavastatin Cmax
Atazanavir Pitavastatin 4 mg daily + Atazanavir 300 mg daily for 5
↑ 31% ↑ 60%
days

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 Pitavastatin Monograph

Cyclosporine Pitvastatin 2 mg daily for 6 days + Cyclosporine 2 mg/kg

↑ 4.6 fold ↑ 6.6 fold
on Day 6
Digoxin Pitavastatin 4 mg daily + Digoxin 0.25 mg daily for 7 days ↑ 4% ↓ 9%
Enalapril Pitavastatin 4 mg daily + Enalapril 20 mg daily for 5 days ↑ 6% ↓ 7%
Erythromycin Pitavastatin 4 mg single dose on Day 4 + Erythromycin
↑ 2.8 fold ↑ 3.6 fold
500 mg 4 times daily for 6 days
Ezetimibe Pitavastatin 2 mg daily + Ezetimibe 10 mg daily for 7 days ↓ 2% ↓ 0.2%
Fenofibrate Pitavastatin 4 mg daily + Fenofibrate 160 mg daily for 7
↑ 18% ↑ 11%
days
Gemfibrozil Pitavastatin 4 mg daily + Gemfibrozil 600 mg BID for 7
↑ 45% ↑ 31%
days
Grapefruit Juice 1,45
Pitavastatin 2 mg single dose on Day 3 + Grapefruit juice
↑ 13-15% ↓ 12%
for 4 days
Itraconazole Pitavastatin 4 mg single dose on Day 4 + Itraconazole
↓ 23% ↓ 22%
200 mg daily for 5 days
Rifampin Pitavastatin 4 mg daily + Rifampin 600 mg daily for 5
↑ 2.8 fold ↑ 3.6 fold
days
Ritonavir/Lopinavir Pitavastatin 4 mg daily on Days 1-5 and 20-24 +
↓ 20% ↓ 4%
Ritonavir/Lopinavir 100/400 mg BID on Days 9 – 24

Table 9. Effect of Pitavastatin Co-Administration on Systemic Exposure to Other Drugs

Concomitant Change in other Change in other
Dose Regimen
Drug drug AUC drug Cmax
Atazanavir Pitavastatin 4 mg daily + Atazanavir 300 mg daily for
↑ 6% ↑ 13%
5 days
Digoxin Pitavastatin 4 mg daily + Digoxin 0.25 mg daily for 7
↓ 3% ↓ 4%
days
Enalapril Pitavastatin 4 mg daily + Enalapril 20 mg daily for 5
↑ 12% ↑ 12%
days
Ezetimibe Pitavastatin 2 mg daily + Ezetimibe 10 mg daily for 7
↑ 9% ↑ 2%
days
Lopinavir Pitavastatin 4 mg daily on Days 1-5 and 20-24 +
↓ 9% ↓ 7%
Ritonavir/Lopinavir 100/400 mg BID on Days 9 – 24
Rifampin Pitavastatin 4 mg daily + Rifampin 600 mg daily for 5
↓ 15% ↓ 18%
days
Ritonavir Pitavastatin 4 mg daily on Days 1-5 and 20-24 +
↓ 11% ↓ 11%
Ritonavir/Lopinavir 100/400 mg BID on Days 9 – 24
Warfarin Individualized maintenance dose
of warfarin (2 – 7 mg) for 8 days R-warfarin ↑ 7% ↑ 3%
+ Pitavastatin 4 mg daily for 9
days S-warfarin ↑ 6% ↑ 3%

Acquisition Costs
The cost for each pitavastatin 1, 2, and 4 mg tablet is approximately $2.264, $2.286, and $2.302,
respectively. The cost for a 90-day bottle of the 1, 2, and 4 mg strengths is approximately $203.73,
$205.77, and $207.18, respectively. See Table 10 for costs of other statins.
Table 10. Statin Acquisition Costs*
Drug Dose+ Cost/Day/Patient ($) Cost/90 Days/Patient ($) Cost/Year/Patient ($)
1 mg daily 2.264 203.73 824.90
2 mg daily 2.286 205.77 832.20
4 mg daily 207.18
2.302 839.50
Pitavastatin
Lovastatin (formulary) 40-80 mg 0.08-0.16 7.20-14.40 29.20-58.40
Simvastatin (formulary) 20-40 mg 0.06 5.40-10.80 21.90-43.80
Pravastatin (formulary) 40-80 mg 0.08-0.14 7.20-12.60 29.20-51.10
Atorvastatin 10-20 mg 1.84-2.6 165.60-234 671.60-949
Fluvastatin 40 mg 1.77 159.30 646.05
Fluvastatin XL 80 mg 2.26 203.40 821.25
Rosuvastatin 5-10 mg 0.79 71.10 288.35
*VA prices as of November 30, 2011; check VA pricing sources for the most up to date information (Prices do not
reflect tablet splitting)
+
Pitavastatin 2 mg daily produces a similar mean % reduction from baseline as: Simvastatin 20 mg, Lovastatin 40 mg,
Pravastatin 40-80 mg, Atorvastatin 10 mg, Fluvastatin 40-80 mg, Rosuvastatin 5 mg

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 Pitavastatin Monograph

+
Pitavastatin 4 mg daily produces a similar mean % reduction from baseline as : Simvastatin 40 mg, Lovastatin 80 mg,
Pravastatin 80 mg, Atorvastatin 20 mg, Fluvastatin 80 mg, Rosuvastatin 5 mg.

Table 11. Statin Utilization (August-October 2011)

Statin (All doses combined) Unique Patients
Pitavastatin 28
Lovastatin 34,703
Simvastatin 1,172,010
Pravastatin 156,793
Atorvastatin 16,435
Fluvastatin 917
Fluvastatin XL 633
Rosuvastatin 292,522

Pharmacoeconomic Analysis
There are no published pharmacoeconomic evaluations of pitavastatin to date.

Conclusions
Pitavastatin is the latest statin to be approved in the United States. Daily doses range from 1-4 mg daily.
The reduction in LDL is approximately 41-45% when dosed at the maximum recommended dose of 4 mg
once daily (data from 10 active comparator studies). At this time, there are no published studies assessing
the effect of pitavastatin on major adverse cardiovascular events as the primary outcome measure.

There have been several randomized active comparator trials that were done to evaluate the safety and
efficacy of pitavastatin. These trials have shown a similar LDL lowering efficacy between pitavastatin 2
mg, atorvastatin 10 mg, and simvastatin 20 mg.

The effect of pitavastatin vs. atorvastatin on atherosclerotic plaque progression was examined in a fifty-two
week, open-label trial (n=307) conducted in Japanese patients presenting with ACS. In this study,
pitavastatin reduced plaque volume similar to atorvastatin (as assessed by IVUS) and the incidence of
major adverse cardiovascular events occurred at a similar rate in patients receiving either atorvastatin or
pitavastatin. At this time, there are no published, large, long-term, controlled studies examining the effect
of pitavastatin on cardiovascular events. However, there are at least two ongoing, unblinded studies 46-47
examining the effect of pitavastatin on cardiovascular outcomes: 1) comparing 1 mg to 4 mg of pitavastatin
in Japanese individuals with stable coronary artery disease 46, 2) comparing 2 mg vs. 4 mg of pitavastatin in
Korean patients after a myocardial infarction.47

Pitavastatin is generally well tolerated. In premarketing trials, the most common adverse events included
back pain (1.4-3.9%), gastrointestinal (GI) distress (1.5-3.6%), elevated creatine phosphokinase (0.6%;
CPK) and myalgia (0.5%) with the latter two generally occurring more often with the highest dose. This is
consistent with post-marketing data where the most common side effects were creatine kinase elevations
(1-6%; CK), dizziness (4%), nasopharyngitis (5.4%), headache (3%) and GI upset (2%). Reports of
myalgia and clinically significant increases in liver function tests (LFTs) were noted to be as high as 4%
and 7.4%, respectively.1-7 Although the exact incidence is unknown, the most severe but rare side effects of
pitavastatin include hypersensitivity reactions and rhabdomyolysis. The safety of pitavastatin was assessed
in a two-year post-marketing surveillance study conducted in clinical practice in Japan (n=19,925). 8 In that
study, authors noted that approximately 10.4% of patients experienced an adverse event which required
discontinuation in 7.4% of cases. Of the reported adverse events, one percent were classified as severe and
included abnormal liver function (4 events), liver disorder (3 events), cataract operation (3 events), and
AST/ALT increased (4 events). Although these adverse drug events generally resulted in discontinuation of
pitavastatin, there were no reported cases of liver transplant or deaths due to pitavastatin. There was one
reported case of rhabdomyolysis in that study.

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 Pitavastatin Monograph

There are limited safety data beyond 12-16 weeks comparing pitavastatin to placebo or to comparator
statins. In the FDA review of pitavastatin, the medical reviewer noted that significant differences in safety
and/or efficacy were not observed between pitavastatin and low to moderate dose comparator statins.

Pitavastatin is similar to fluvastatin and rosuvastatin in that it is partly metabolized by CYP 2C9 and
therefore is not susceptible to the many drug interactions affecting CYP 3A4. However, it is not entirely
void of significant drug interactions which can result in clinically significant increases in pitavastatin serum
concentrations potentially resulting from an alteration in transporter proteins. As a result, the manufacturer
has recommended dose limits and contraindications for pitavastatin in certain instances (e.g. concomitant
erythromycin or rifampin, moderate-severe renal impairment and avoidance of use in patients receiving
cyclosporine).

Because of the lack of evidence to support an effect on cardiovascular outcomes and the limited safety data
in non-Asian populations compared to the other available statins, pitavastatin should have limited use in
VA.

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Prepared January 2012. Contact person: Michael Gillette, Pharm.D., BCPS and Cathy
Kelley, Pharm.D., BCPS, cathy.kelley@va.gov

Appendix: Clinical Trials

A literature search was performed through PubMed (1948 to October 2011) using the search terms
“pitavastatin”, “itavastatin”, “nisvastatin”, “NK 104”, and “NKS 104” and “Livalo®”. The search was
limited to studies performed in humans and published in English language. Reference lists of review
articles and the manufacturer’s AMCP dossier were searched for relevant clinical trials. All randomized
controlled trials published in peer-reviewed journals were included.

Methods
Literature Search
A search was conducted through PubMed (1948 – October 2011) using the term “pitavastatin”.

Eligibility Criteria and Study Selection

All clinical trials performed in human 13 years of age and older were included

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov 17